17-59964618-C-T

Position:

• chr17-59964618-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016125.4(RNFT1):​c.46G>A​(p.Gly16Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,454,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RNFT1 NM_016125.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.480

Genes affected

RNFT1 (HGNC:30206): (ring finger protein, transmembrane 1) Enables ubiquitin binding activity and ubiquitin protein ligase activity. Involved in positive regulation of ERAD pathway and protein autoubiquitination. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000267318 (HGNC:):

TBC1D3P1-DHX40P1 (HGNC:42362): (TBC1D3P1-DHX40P1 readthrough, transcribed pseudogene) This locus represents naturally-occurring readthrough transcription that extends through two unprocessed pseudogenes, TBC1D3P1 (TBC1 domain family member 3 pseudogene 1) and DHX40P1 (DEAH-box helicase 40 pseudogene 1), to protein-coding RNFT1 (ring finger protein, transmembrane 1). The individual pseudogene loci are not curated as transcribed regions. The readthrough transcript likely does not encode a functional protein, since translation of the long open reading frames would render the transcript a candidate for nonsense-mediated decay (NMD). [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.089410216).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNFT1	NM_016125.4	c.46G>A	p.Gly16Ser	missense_variant	1/9	ENST00000305783.13	NP_057209.3
TBC1D3P1-DHX40P1	NR_002924.3	n.1207-1334G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNFT1	ENST00000305783.13	c.46G>A	p.Gly16Ser	missense_variant	1/9	1	NM_016125.4	ENSP00000304670.8
ENSG00000267318	ENST00000591035.1	c.150-1785C>T		intron_variant		3		ENSP00000468280.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454512 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722862

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000254 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 26, 2024

The c.46G>A (p.G16S) alteration is located in exon 1 (coding exon 1) of the RNFT1 gene. This alteration results from a G to A substitution at nucleotide position 46, causing the glycine (G) at amino acid position 16 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0038	T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.089	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.28	N;.
REVEL	Benign	0.038
Sift	Benign	0.60	T;.
Sift4G	Benign	0.85	T;T
Polyphen		0.079	B;.
Vest4		0.17
MutPred		0.15		Gain of phosphorylation at G16 (P = 0.0075);Gain of phosphorylation at G16 (P = 0.0075);
MVP		0.16
MPC		0.55
ClinPred		0.64	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.050
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs764154452; hg19: chr17-58041979;